External genital warts and perianal warts, i.e., condylomata acuminate, are caused by infection with human papilloma virus (HPV), the most common sexually transmitted virus in the Western world. See, e.g., Lyttle P H.: Surveillance report: disease trends at New Zealand sexually transmitted disease clinics 1977-1993. Genitourin Med., 70:329-335 (1994); Mayeaux E J, Harper M B, Barksdale W, Pope J B.: Noncervical human papillomavirus genital infections. Am Fam Physician., 52:1137-1146 (1995); and Shah K V, Howley P M.: Papillomaviruses. In: Fields, B N, Knipe D M, ed Fields Virology. 2nd ed. New York, N.Y.: Raven Press; (2)59:1651-1666 (1990). Approximately 1% of the sexually active population between 15 and 49 years of age in the United States is estimated to have external genital warts. See, e.g., Koutsky L.: Epidemiology of human papillomavirus infection. Epidemiol Rev., 10:122-163 (1998); and Koutsky L.: Epidemiology of genital human papillomavirus infection. Am J Med., 102(5A):3-8 (1997). Most external genital warts are associated with HPV types 6 and 11. See, e.g., Phelps W, Alexander K A.: Antiviral therapy for human papillomaviruses: rationale and prospects. Ann Intern Med., 123:368-382 (1995). HPV types 6 and 11 are typically labeled as low risk because infection with these types has low oncogenic potential and usually results in the formation of condylomata and low-grade precancerous lesions. See, e.g., Gearhart, P. A. and Randall, T. C.: Human Papillomavirus, emedicine, pages 1-33, http://emedicine.medscape.com/article/219110 (Updated: Mar. 8, 2010); and Fact Sheet: Human Papillomaviruses and Cancer: Questions and Answers, National Cancer Institute, pages. 1-11, www.cancer.gov/cancertopics/factsheet/RiskHPV (Reviewed Feb. 14, 2008).
Specific antiviral therapy for the treatment of external genital warts and perianal warts is lacking, but drug and other therapies have been used. Ablative treatment modalities include procedures such as surgical excision, laser therapy, and cryotherapy. Other approaches include topical treatments, such as acetic acid, podophylline, podophyllotoxin, and 5-fluorouracil, which are cytodestructive, and sinecatechins, whose mechanism of action is unknown. Each of these therapies have disadvantages such as inconvenient regimens, pain, burning associated with the therapy, scarring, itching and/or high recurrence rates.
On Feb. 27, 1997, imiquimod 5% cream was approved for the very first time by the U.S. Food and Drug Administration (FDA) for the treatment of external genital and perianal warts, i.e., condyloma acuminate (EGW or EGWs), in patients 12 years or older. See Aldara® Package Insert (Label) Revised: March 2007 (Attachment VIII). Imiquimod, an immune response modifier that stimulates the innate and adaptive immune response, has been demonstrated to be an effective and safe treatment for external genital warts and perianal warts. Stimulation of the immune response has been shown to decrease IIPV viral load, Kreuter A, Brockmeyer N H, Weissenborn S J, et al.: 5% Imiquimod suppositories decrease the DNA load of intra-anal HPV types 6 and 11 in HIV-infected men after surgical ablation of condylomata acuminata [letter]. Arch Dermatol.; 142(2):243-4 (February, 2006), and thus may decrease the recurrence rate of visible warts, although observed rates after treatments do vary.
In the treatment of EGWs diagnosed in adults, the approved dosing regimen for Aldara® (imiquimod) 5% cream is 3 times per week, for up to 16 weeks of treatment. Aldara® (imiquimod) 5% cream should be applied 3 times per week to external genital/perianal warts. Aldara® (imiquimod) 5% cream treatment should continue until there is total clearance of the genital/perianal warts or for a maximum of 16 weeks. Examples of 3 times per week application schedules are: Monday, Wednesday, Friday or Tuesday, Thursday, Saturday. Aldara® (imiquimod) 5% cream should be applied prior to normal sleeping hours and left on the skin for 6-10 hours, after which time the cream should be removed by washing the area with mild soap and water. The prescriber should demonstrate the proper application technique to maximize the benefit of Aldara® (imiquimod) 5% cream therapy. It is recommended that patients wash their hands before and after applying Aldara® (imiquimod) 5% cream.
A study in 22 patients with genital/perianal warts comparing Aldara® (imiquimod) 5% cream and vehicle shows that Aldara® (imiquimod) 5% cream induces mRNA encoding cytokines including interferon-α at the treatment site. In addition, HPVL1 mRNA and HPV DNA are significantly decreased following treatment. However, the clinical relevance of these findings is unknown.
A thin layer of Aldara® (imiquimod) 5% cream should be applied to the wart area and rubbed in until the cream is no longer visible. The application site should not be occluded. Following the treatment period, the Aldara® (imiquimod) 5% cream should be removed by washing the treated area with mild soap and water. Local skin reactions at the treatment site are common. A rest period of several days may be taken if required by the patient's discomfort or severity caused by the treatment-related local skin reactions. Treatment may resume once the reactions subside. Non-occlusive dressings such as cotton gauze or cotton underwear may be used in the management of skin reactions. Aldara® (imiquimod) 5% cream is currently packaged in single-use packets or sachets which contain sufficient cream to cover a wart area of up to about 20 cm2. Use of excessive amounts of cream and passive transfer of the cream should be avoided.
Actinic keratosis is a precancerous (premalignant) skin disorder caused by or associated with chronic exposure to radiant energy, such as sunlight. Actinic keratosis lesions (AKs) are small, red, rough spots or lesions occurring on sun exposed areas of the skin. Actinic keratosis lesions possess many of the same cellular changes observed in a skin cancer called squamous cell carcinoma (SCC). Research shows that a mutated version of the p53 gene is found in sun-damaged cells in the body and is present in more than about 90% of people who have AKs and SCC. Although most actinic keratosis lesions do not actually become cancerous, some AKs can become malignant.
It is believed that actinic keratosis develops in skin cells called “keratinocytes”, which are the cells that constitute about 90% of the epidermis, the outermost layer of skin. Chronic sun exposure, over time, generates mutations in these cells and causes the cells to change in size, shape, the way they are organized, and the way they behave. In addition, the cellular damage can even extend to the dermis, the layer of skin beneath the epidermis.
Actinic keratosis lesions generally measure in size between about 2 to about 6 millimeters in diameter. AK lesions can range in color from skin-toned to reddish and often have a white scale on top. On occasion, AK lesions will form into the shape of animal horns. When this occurs, the AKs are known as “cutaneous horns.”
People who are at higher risk for developing actinic keratosis tend to be fair-skinned and spend significant time outdoors, e.g., at work or at play, over the course of many years. AKs usually develop on those areas of the body that have been constantly exposed to the sun for years. Additionally, the skin often becomes wrinkled, mottled, and discolored from chronic sun exposure. Common locations for AKs include the face, ears, lips, balding scalp, back of the neck, upper chest, the tops of the hands and forearms. When AKs develop on the lips, the condition is known as actinic cheilitis. Actinic cheilitis can be characterized by a diffuse scaling on the lower lip that cracks and dries. In some cases, the lips will have a whitish discoloration on the thickened lip.
Actinic keratosis is generally more common after age 40, because actinic keratosis takes years to develop. However, even younger adults may develop actinic keratosis when living in geographic areas that are exposed to high-intensity sunlight year round, such as Florida and Southern California.
Actinic keratosis has become a significant health care issue in the United States of America. It is estimated that over 20 million Americans suffer from actinic keratoses, and that that number continues to grow. In fact, actinic keratosis is so common today that treatment for actinic keratosis ranks as one of the most frequent reasons people consult dermatologists.
Once an immunocompetent adult is diagnosed with clinically visible AKs, a variety of treatment options are currently available. These options include physically removing the AKs by (1) freezing them with liquid nitrogen, (2) using a laser to burn the AKs, (3) scraping the AKs off, or (4) using topical creams to treat the AKs. One such cream that can be applied to the skin for the treatment of AKs is Aldara® (imiquimod) 5% cream.
On Mar. 2, 2004, Aldara® (imiquimod) 5% cream was approved by the FDA, under section 505(b) of the Federal Food, Drug and Cosmetic Act, for the treatment of clinically typical, nonhyperkeratotic, nonhypertrophic actinic keratoses on the face and scalp in immunocompetent adults. Imiquimod, an immune response modifier that stimulates the innate and adaptive immune response, has been demonstrated to be an effective and safe treatment for AKs. Aldara® (imiquimod) 5% cream works from within by activating the adult's own immune system to treat disease.
In the treatment of adults diagnosed with actinic keratosis, the approved dosing regimen for Aldara® (imiquimod) 5% cream is 2 times per week, for a full 16 weeks to a defined treatment area on the face or scalp (but not both concurrently). See Aldara® Package Insert (Label) Revised: March 2007 (Attachment VIII).
According to the approved Aldara® Package Insert (Label) Revised: March 2007 (Attachment VIII), the treatment area is defined as one contiguous area of up to approximately 25 cm2 (e.g., 5 cm×5 cm) on the face (e.g. forehead or one cheek) or on the scalp, and examples of 2 times per week application schedules are Monday and Thursday, or Tuesday and Friday. The Aldara® Package Insert (Label) Revised: March 2007 (Attachment VIII) further instructs that the Aldara® (imiquimod) 5% cream should be applied to the entire treatment area and rubbed in until the cream is no longer visible. The Aldara® Package Insert (Label) Revised: March 2007 (Attachment VIII) cautions that no more than one packet of Aldara® (imiquimod) 5% cream should be applied to the contiguous treatment area at each application, and the Aldara® (imiquimod) 5% cream should be applied prior to normal sleeping hours and left on the skin for approximately 8 hours, after which time the cream should be removed by washing the area with mild soap and water.
The Aldara® Package Insert (Label) Revised: March 2007 (Attachment VIII) further advises that prescribers should demonstrate the proper application technique to maximize the benefit of Aldara® (imiquimod) 5% cream therapy.
The Aldara® Package Insert (Label) Revised: March 2007 (Attachment VIII) also recommends that patients should wash their hands before and after applying the Aldara® (imiquimod) 5% cream as well as the treatment area with mild soap and water and allow the area to dry thoroughly (at least 10 minutes) before applying Aldara® (imiquimod) 5% cream.
The Aldara® Package Insert (Label) Revised: March 2007 (Attachment VIII) further cautions that contact with the eyes, lips and nostrils should be avoided and warns that Aldara® (imiquimod) 5% cream is not for oral, ophthalmic, or intravaginal use.
Because the Aldara® (imiquimod) 5% cream is currently packaged in single-use packets, with 12 packets supplied per box, the Aldara® Package Insert (Label) Revised: March 2007 (Attachment VIII) instructs that patients should be prescribed no more than 3 boxes (36 packets) for the 16-week treatment period, and that unused packets should be discarded. The Aldara® Package Insert (Label) Revised: March 2007 (Attachment VIII) clearly warns that partially-used packets should be discarded and not reused.
Aldara® (imiquimod) 5% cream is also FDA approved to treat superficial basal cell carcinoma (sBCC), a form of skin cancer. See, e.g., Aldara® Package Insert (Label) Revised: March 2007 (Attachment VIII).
Skin cancer can occur anywhere on the body. Skin cancer, however, is most commonly diagnosed on skin that, like with AKs, has been in constant exposure to intense sunlight, especially during childhood or young adulthood. According to the American Cancer Society, the most common type of skin cancer is basal cell carcinoma (BCC), affecting about 800,000-900,000 Americans each year.
BCC develops within the basal cells, which are found within the basal layer of the epidermis or the top layer of the skin. Basal cells are typically small and round and continually divide to produce new skin cells and replace old ones.
BCC is typically a slow growing disease which can metastasize to other areas of the body including the lymph nodes, bone or other tissues beneath the skin if left untreated. Basal cell carcinoma occurs most often on sun exposed areas of the skin such as the head or neck. Although basal cell carcinoma rarely spreads to other parts of the body, it may cause local tissue destruction and it can be very destructive and disfiguring.
There are several types of BCC, including nodular basal cell carcinoma, superficial basal cell carcinoma (sBCC), small basal cell carcinoma, morpheaform basal cell carcinoma, infiltrating basal cell carcinoma, pigmented basal cell carcinoma, micronodular basal cell carcinoma and cystic basal cell carcinoma, each of which manifests a different pattern of behavior.
If allowed to progress without treatment, BCC can cause clinically significant morbidity. Because BCC most commonly affects the head and neck, cosmetic disfigurement is common. In addition, if there is orbital involvement, loss of vision or even loss of an eye may occur. BCC lesions are prone to ulceration and infection and, if there is perineural spread or deep and extensive skin invasion, nerve function can be lost. Death from BCC, however, is uncommon.
A history of chronic recreational or occupational sun exposure is typically observed in patients diagnosed with basal cell carcinoma. Common symptoms presented at diagnosis include lesions or sores that (a) won't heal, (b) vary in duration, and (c) often bleed when exposed to mild trauma, such as towel washing or drying.
Because there are several subtypes of BCC, it is critical for the health care provider to recognize and distinguish between the various subtypes in order to prescribe appropriate therapy. For example, aggressive therapy is often necessary for variants such as micronodular, infiltrating, morpheaform and superficial basal cell carcinoma.
Superficial basal cell carcinoma (sBCC) is one subtype of basal cell carcinoma. sBCC is the most common form of skin cancer, but it is readily treatable if identified and treated early. sBCC is generally diagnosed by a healthcare provider after biopsy. Typically, sBCC slowly progresses and clinically appears as erythematous eruptions or lesions. sBCC lesions may appear as new growths on the skin, as open sores that fail to heal, or as changes in appearance of an old growth on the skin. Generally, however, the sBCC lesions are usually not painful and may have different shapes and colors. sBCC lesions often present as pink to red-brown scaly patches or papules with a whitish scale. The sBCC lesions appear multicentric wherein clinically normal skin and clinically involved skin often intervene or commingle. The sBCC patches or papules may mimic eczema or psoriasis. sBCC skin changes to look for include the following:                A small, smooth, shiny lump that may be pale or waxy        A firm, red lump;        A sore or lump that bleeds or is covered by a scab; and/or        A red or brown patch that is rough or scaly and may itch or become tender.        
sBCC is usually treated by surgical removal.
On Jul. 14, 2004, the FDA approved the use of Aldara® (imiquimod) 5% cream under biopsy-confirmed, primary superficial basal cell carcinoma (sBCC) in immunocompetent adults, with a maximum tumor diameter of 2.0 cm, located on the trunk (excluding anogenital skin), neck, or extremities (excluding hands and feet), only when surgical methods are medically less appropriate and patient follow-up can be reasonably assured. According to the Aldara® Package Insert (Label) Revised: March 2007 (Attachment VIII), the histological diagnosis of sBCC should be established prior to treatment with Aldara® (imiquimod) 5% cream, because Aldara® (imiquimod) 5% cream at that time was not approved for the treatment of other types of basal cell carcinomas, such as nodular and morpheaform (fibrosing or sclerosing) types.
In the treatment of sBCC diagnosed in adults, the approved dosing regimen for Aldara® (imiquimod) 5% cream is 5 times per week for a full 6 weeks to a biopsy-confirmed superficial basal cell carcinoma. See Aldara® Package Insert (Label) Revised: March 2007. An example of a 5 times per week application schedule is to apply Aldara® (imiquimod) 5% cream, once per day, Monday through Friday, for six full weeks. Aldara® (imiquimod) 5% cream should be applied prior to normal sleeping hours and left on the skin for approximately 8 hours, after which time the cream should be removed by washing the area with mild soap and water.
According to the Aldara® Package Insert (Label) Revised: March 2007, the prescriber should demonstrate the proper application technique to maximize the benefit of Aldara® (imiquimod) 5% cream therapy.
It is also recommended in the Aldara® Package Insert (Label) Revised: March 2007 that patients should wash their hands before and after applying Aldara® (imiquimod) 5% cream and that the patient should wash the treatment area with mild soap and water and allow the area to dry thoroughly before applying the cream.
According to the Aldara® Package Insert (Label) Revised: March 2007, the target sBCC tumor should have a maximum diameter of 2 cm and be located on the trunk (excluding anogenital skin), neck, or extremities (excluding hands and feet). Also according to the Aldara® Package Insert (Label) Revised: March 2007, the treatment area should include a 1 cm margin of skin around the tumor, and that sufficient cream should be applied to cover the treatment area, including 1 centimeter of skin surrounding the tumor. The Aldara® Package Insert (Label) Revised: March 2007 further instructs that the Aldara® (imiquimod) 5% cream should be rubbed into the treatment area until the cream is no longer visible.
As reported in the Aldara® Package Insert (Label) Revised: March 2007, the amount of Aldara® (imiquimod) 5% cream that should be used to treat sBCC is reproduced in Table 1 as follows.
TABLE 1Amount of Aldara ® Cream to Use for sBCCTarget TumorSize of Cream DropletApproximate Amount ofDiameterto be Used (diameter)Aldara ® to be Used 0.5 to <1.0 cm4 mm10 mg. 1.0 to <1.5 cm5 mm25 mg . 1.5 to 2.0 cm7 mm40 mg
According to the Aldara® Package Insert (Label) Revised: March 2007, contact with the eyes, lips and nostrils should be avoided and warns that Aldara® (imiquimod) 5% cream is not for oral, ophthalmic or intravaginal use.
Aldara® (imiquimod) 5% cream is packaged in single-use packets or sachets, with 12 packets supplied per box. Patients should be prescribed no more than 3 boxes (36 packets) for the 6-week treatment period. Unused packets and partially-used packets should be discarded and not reused. See Aldara® Package Insert (Label) Revised: March 2007 (Attachment VIII).
Thus, to date, the FDA has approved imiquimod 5% cream, commercially available under the brand name Aldara®, to treat dermal and/or mucosal-associated conditions, namely, the topical treatment of: (1) external genital and perianal warts, i.e., condyloma acuminate, in patients 12 years or older; (2) clinically typical, nonhyperkeratotic, nonhypertrophic AKs on the face or scalp in immunocompetent adults; and (3) biopsy-confirmed, primary sBCC in immunocompetent adults.
More recently, lower dosage strength formulations of imiquimod cream have been developed for use in effectively treating AKs and EGWs, which contain imiquimod in an amount by weight of between about 1% to about 4.25%, and preferably about 2.5% or about 3.75%. In conjunction with these lower dosage strength formulations, the treatment regimens for AKs and EGW have been uniquely shortened and simplified. These reduced dosage strength formulations and modified treatment regimens are disclosed in (1) U.S. patent application Ser. No. 12/636,613, (2) U.S. patent application Ser. No. 12/771,076, (3) PCT Publication No. WO/2010/080345, (4) PCT International Application No. PCT/US2009/067759, (5) PCT International Application No. PCT/US2010/33245, (6) Canadian Patent No. 2,649,893, issued on Aug. 3, 2010 and entitled “Lower Dosage Strength Imiquimod Formulations and Short Dosing Regimens for treating Actinic Keratosis”, (7) the Zyclara® Package Insert (Label) (Attachment IX) for AK treatment with Zyclara® (imiquimod) 3.75% cream, (8) the proposed Zyclara® Package Insert (Label) (Attachment X) submitted to the FDA for EGW treatment with Zyclara® (imiquimod) 3.75% cream, (9) the Zyclara® Canada Product Monograph (Attachment XI) for AK treatment with Zyclara® (imiquimod) 3.75% cream, (10) the proposed Zyclara® Canada Product Monograph (Attachment XII) submitted to Health Canada for EGW treatment with Zyclara® (imiquimod) 3.75% cream, (11) the proposed Zyclara® Package Insert (Label) (Attachment XIII) for submission to the FDA for AK treatment with a pump pre-filled with Zyclara® (imiquimod) 3.75%, (12) the proposed Zyclara® Canada Product Monograph (Attachment XIV) for submission to Health Canada for AK treatment with a pump pre-filled with Zyclara® (imiquimod) 3.75%, and (13) the draft Zyclara® Package Insert (Label) (Attachment XV) for submission to the FDA for AK treatment with a pump pre-filled with Zyclara® (imiquimod) 2.5% cream, each of which is incorporated herein by reference in its entirety.
As discussed in U.S. patent application Ser. No. 12/771,076, and PCT International Application No. PCT/US2010/33245, a patient diagnosed with EGW can apply an effective amount of a lower strength formulation of imiquimod cream, such as a 2.5% or a 3.75% w/w formulation, to the wart area once a day for up to 8 weeks to achieve at least partial, if not complete, clearance of the wart.
Results from a Phase III program evaluating imiquimod 3.75% and 2.5% creams for the treatment of EGW, applied once daily for up to 8 weeks, demonstrated that both dosage strengths were well-tolerated and more efficacious than placebo. According to investigators conducting the study, strong efficacy results with the 3.75% unique formulation along with an enhanced safety profile were observed. More specifically, of those who achieved initial complete clearance and entered the 12-week follow-up, complete clearance was sustained in about 69.6% of the subjects on Zyclara® (imiquimod) 3.75% cream. As to the safety profile, a low incidence of treatment-related adverse events such as itching (2.5%), burning (5.8%) or pain (6.8%) at the application sites were observed, and no treatment-related reported systemic adverse events of headache or flu-like symptoms were observed. These surprising data were included in a New Drug Application (NDA) accepted for review by the FDA for the use of Zyclara® (imiquimod) 3.75% cream in an eight-week treatment regimen for the treatment of EGW.
With respect to AK treatment, the FDA, on Mar. 30, 2010, approved a topical 3.75% imiquimod pharmaceutical cream, commercially available under the brand name Zyclara®, to treat clinically visible or palpable actinic keratosis lesions (AKs), of the full face or balding scalp in immunocompetent adults. This newly approved dosing regimen with Zyclara® (imiquimod) 3.75% cream to treat AKs is a novel 6-week treatment regimen involving three cycles, that are equal in duration. In the first cycle of the 6-week treatment regimen, the Zyclara® (imiquimod) 3.75% cream is applied daily for two weeks to the targeted area, i.e., the full face or balding scalp diagnosed with AKs. In the second cycle of the 6-week treatment regimen designated as a rest period cycle, the Zyclara® (imiquimod) 3.75% cream is not applied to the targeted area. In the third or final cycle of the 6-week treatment regimen, the Zyclara® (imiquimod) 3.75% cream is again applied daily for two weeks to the targeted area. This unique 6-week treatment regimen to treat AKs with Zyclara® (imiquimod) 3.75% cream is referred to as a “2-week×2-week×2-week” or simply a “2×2×2” treatment regimen. See Zyclara® Package Insert (Label) (Attachment IX) attached hereto. See also the proposed Zyclara® Package Insert (Label) for Zyclara® (imiquimod) 2.5% cream to treat AKs in accordance with the 2×2×2″ treatment cycle (Attachment XV).
Alternatively, a unique 9-week treatment regimen may be employed to treat AKs with Zyclara® (imiquimod) 3.75% cream or Zyclara® (imiquimod) 2.5% cream, wherein the 9 week treatment regimen involves three cycles as follows: “3-week×3-week×3-week” or simply a “3×3×3” treatment regimen. Like with the 2×2×2 treatment regimen, the Zyclara® cream is applied daily to the targeted or treatment area in the first and third cycles, i.e., applied daily during the first and last 3-week cycles. However, during the second or middle 3-week cycle, it too is a rest period wherein no Zyclara® cream is applied during the second cycle.
One of the unique benefits associated with this new and improved treatment regimen, the Zyclara® (imiquimod) 3.75% cream serendipitously treats sub-clinical AKs (not clinically visible—not initially detected) located in the targeted treatment area at the same time of treatment of clinically visible AKs. Because the Zyclara® (imiquimod) 3.75% cream is applied to the “entire” face or “entire” balding scalp diagnosed with clinically visible AKs, unlike with current Aldara® treatment, the sub-clinical AKs within such treatment area are simultaneously treated with the Zyclara® (imiquimod) 3.75% cream during this “2×2×2” treatment regimen of the clinically visible AKs. These previously unseen AKs, that could appear during treatment, may therefore clear before they have a chance to develop further as a result of this unique “2×2×2” treatment regimen with Zyclara® (imiquimod) 3.75% cream.
The drug imiquimod, contained in both Aldara® and Zyclara®, is an immune response modifier. Chemically, imiquimod is known as 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-4-amine or 1-isobutyl-1H-imidazo[4,5-c]-quinolin-4-amine. Imiquimod has a molecular formula of C14H16N4 and a molecular weight of 240.3. The chemical structural formula for imiquimod is as follows:

Common to each of the FDA-approved treatments with imiquimod for treating EGWs, AKs and sBCC, the correct amount of cream or a specific unit dose to be applied each time by the patient is required for effective therapy. Also common to each of such FDA-approved treatments with imiquimod, is the inconvenient and imprecise use of single-use packets or sachets to apply the topical imiquimod pharmaceutical creams to the treatment areas.
For example, if the Aldara® (imiquimod) 5% cream or Zyclara® (imiquimod) 3.75% cream is applied too thickly or generously, the over dosage can exacerbate unwanted site reactions or local skin reactions, such as erosions or ulcerations, causing pain or dysfunction (e.g., of the foreskin or urethra), and cause undesirable systemic absorption of the imiquimod leading to flu-like symptoms and headaches. Moreover, if the patient is not careful, the patient will inadvertently apply residual Aldara® (imiquimod) 5% cream or Zyclara® (imiquimod) 3.75% cream to other areas of the body compounding over dosage issues that can further exacerbate the unwanted side effects.
If, however, too little imiquimod cream is applied to the targeted areas, the patient may not achieve the maximum level or even an effective level of therapeutic benefit.
Also common to each of the FDA-approved treatments with imiquimod for treating EGW, AK and sBCC, the pharmaceutical concentration and stability of the imiquimod formulation provided to the patient must be maintained throughout the duration of the treatment, which could be for as long as 16 weeks when treating EGWs and AKs with Aldara® (imiquimod) 5% cream or for up to 8 weeks when treating EGWs with Zyclara® 3.75% (imiquimod) cream or for up to 6 weeks when treating sBCC with Aldara® (imiquimod) 5% cream. Thus, the storage devices should not adversely impact the stability, uniformity, dosing concentration or dosing technique of the pre-filled topical semi-solid imiquimod pharmaceutical formulation.
Each gram of Aldara® (imiquimod) 5% cream contains 50 mg of imiquimod and each gram of the Zyclara® (imiquimod) 3.75% cream contains 37.5 mg of imiquimod. The Aldara® (imiquimod) 5% cream and the Zyclara® (imiquimod) 3.75% cream are each formulated in an off-white oil-in-water vanishing cream base consisting of isostearic acid, cetyl alcohol, stearyl alcohol, white petrolatum, polysorbate 60, sorbitan monostearate, glycerin, xanthan gum, purified water, benzyl alcohol, methylparaben, and propylparaben. The Aldara® (imiquimod) 5% cream is packaged in single-use packets or sachets, each containing 250 mg of cream, equivalent to 12.5 mg of imiquimod. The Zyclara® (imiquimod) 3.75% cream is packaged in single-use packets or sachets, each containing 250 mg of cream, equivalent to 9.375 mg of imiquimod.
Unfortunately, single-use packets or sachets pre-filled with an imiquimod pharmaceutical cream are not without drawback. There are several disadvantages associated with providing an imiquimod pharmaceutical cream to a patient in a single-use packet or sachet. Single-use packets or sachets pre-filled with a topical imiquimod pharmaceutical cream are, for example, notoriously messy, difficult and clumsy to use, and more importantly notably imprecise. These known drawbacks can lead to needless product waste, overdosing, inadequate dosing, failed compliance, contamination and/or passive (unintended) transfer to other areas of the patients' bodies, such as the eyes, ears, nose, mouth and vagina.
To underscore these drawbacks, patients often fail to apply the appropriate dosage amount or to ensure that all of the imiquimod cream is squeezed out of the single-use packet or sachet during application to the treatment area. Consequently, patients are frequently under-dosed or over-dosed, which can lead to poor patient compliance.
This problem is recognized in the FDA-approved Labels and Health Canada-approved Labels for both the Aldara® (imiquimod) 5% cream and the Zyclara® (imiquimod) 3.75% cream, as well as in the proposed FDA Labels and Health Canada Labels for the Zyclara® (imiquimod) 3.75% cream and in the draft FDA-Label for Zyclara® (imiquimod) 2.5% cream, each of which are incorporated herein by reference in their entireties. See, for example, Attachments VIII and XV, respectively. In each of the FDA-approved and FDA-proposed Labels and in each of the Health Canada-approved and Health Canada-proposed Labels, the prescriber is clearly instructed to demonstrate the proper application technique for the Aldara® (imiquimod) 5% cream, the Zyclara® (imiquimod) 3.75% cream and the Zyclara® (imiquimod) 2.5% cream, respectively, to the patients to minimize or avoid these drawbacks. Thus, dosing inconsistencies and product waste associated with single-use packets or sachets pre-filled with a topical imiquimod pharmaceutical cream are problematic, common and cause for concern.
Another drawback associated with single-use packets or sachets pre-filled with a topical imiquimod pharmaceutical cream concerns excessive contact with and improper application technique of the dispensed imiquimod pharmaceutical creams from the single-use packets or sachets by the patients. Because imiquimod is an immune response modifier, minimal patient contact and proper application technique is important to avoid imiquimod cream contamination, imprecise dosing, product waste, passive transfer to other parts of the patient's body that are outside of the treatment area, such as the eyes, ears, nose, mouth and vagina. These problems are also recognized in each of the FDA-approved, Health Canada-approved and proposed Labels wherein each Label (a) instructs the patients to thoroughly wash their hands “before” and “after” imiquimod cream application, (b) cautions that topical imiquimod creams contact with eyes, lips and nostrils should be avoided, and (c) warns that topical imiquimod creams are not for oral, ophthalmic, or intravaginal use. See Attachments VIII-XV, each of which is incorporated herein by reference in its entirety.
In yet another drawback, single-use packets or sachets pre-filled with a topical imiquimod pharmaceutical cream can be very difficult and cumbersome to use, especially when elderly patients are involved. Opening a single-use packet or sachet pre-filled with a topical imiquimod cream to dispense the imiquimod cream to “only” the targeted area without excessive handling or passive transfer can in some instances present real application technique challenge to those patients inflicted with, for example, limited dexterity, crippling arthritis, vision loss and/or visual acuity loss, which are commonly observed in elderly patients.
In still another drawback, needless product waste often occurs with single-use packets or sachets pre-filled with a topical imiquimod cream. Clear instruction to patients provides that undispensed imiquimod cream and unopened individual packets or sachets pre-filled with a topical imiquimod cream must be discarded. This particular drawback is highlighted in all Labels, the FDA-approved and proposed Labels and the Health Canada approved and proposed Labels for Aldara® (imiquimod) 5% cream and Zyclara® (imiquimod) 3.75% cream, respectively. As stated above, and according to such Labels, unopened and partially used single-use packets or sachets pre-filled with a topical imiquimod cream must be discarded and not reused. See Attachments VIII-XII. See also Attachments XIII-XV.
In yet another drawback associated with single-use packets or sachets pre-filled with a topical imiquimod cream, the single use packets or sachets can be easily lost or misplaced due to the fact that several single-use packets or sachets must be purchased to complete a full course of therapy. This drawback and inconvenience can cause further product waste and needless elevated treatment costs due to necessary product replacement. More seriously, this drawback and inconvenience can lead to failed patient compliance and ineffective imiquimod therapy.
In still another drawback associated with such single-use packets or sachets, imiquimod cream degradants may develop over time as a result of storage in the single-use packets or sachets. This drawback can cause an adverse effect on overall efficacy and/or stability of the imiquimod cream formulations packaged within the single-use packets or sachets.
Thus, given the numerous drawbacks associated with single-use imiquimod cream packets or sachets, there is a real need for a simple, safe, clean, easy-to-use, compact, reliable and all-in-one storage system for dispensing topical semi-solid imiquimod pharmaceutical formulations that: (i) can dispense a controlled and precise amount of imiquimod cream each and every time the topical imiquimod formulation is applied to a treatment area, (ii) is easy and convenient for any patient, young or old, to use; (iii) improves imiquimod therapy compliance and effectiveness, (iv) provides the same unit dose, such as approximately 250 mg of imiquimod formulation, per each actuation, i.e., a reproducible dose amount, so that an effective dose is administered each and every time; (v) does not interfere with or hinder imiquimod application technique, (vi) minimizes if not eliminates product waste and product loss, (vii) minimizes if not eliminates excessive patient contact to avoid passive transfer, (viii) minimizes and/or prevents degradant formation during imiquimod formulation storage; and (ix) is compatible for use with topical semi-solid imiquimod formulations, for example, topical 2.5%, 3.75% and 5% weight to weight imiquimod creams, for treating dermal and/or mucosal-associated conditions, such as external genital warts, perianal warts, actinic keratoses and superficial basal cell carcinoma.